Current Perspectives in Polycystic Syndrome MARILYN R. RICHARDSON, M.D., University of Kansas Medical Center, Kansas City, Kansas

Polycystic ovary syndrome has been viewed primarily as a gynecologic disorder requiring medical intervention to control irregular bleeding, relieve chronic , and facil- itate pregnancy. A large body of evidence has demonstrated an association between insulin resistance and polycystic ovary syndrome. The former condition has an estab- lished link with long-term macrovascular diseases such as type 2 diabetes mellitus, hyper- tension, and atherosclerotic heart disease, consequences that also are observed in women with polycystic ovary syndrome. In addition, chronic anovulation predisposes women to and carcinoma. The purpose of this review is to examine the clinical course of this syndrome, which spans adolescence through , and suggest a simple and cost-effective diagnostic evaluation to screen the large numbers of women who may be affected. Therapy, which should be individualized, should incorporate steroid hormones, antiandrogens, and insulin-sensitizing agents. Weight loss by way of reduced carbohydrate intake and gentle exercise is the most important intervention; this step alone can restore menstrual cyclicity and fertility, and provide long-term prevention against diabetes and heart disease. Treatment alternatives should be directed initially toward the most compelling symptom. Longitudinal care is of paramount importance to provide protection from long-term sequelae. (Am Fam Physi- cian 2003;68:697-704. Copyright© 2003 American Academy of Family Physicians.)

olycystic ovary syndrome (PCOS) are well placed to make early diagnoses of is the most common endocri- PCOS and to help patients avoid the long- nopathy among women of repro- term consequences. ductive age and is estimated to affect up to 10 percent of the U.S. Clinical Course Ppopulation or approximately 5 million Young women of reproductive age most fre- women.1 In 1935, Stein and Leventhal2 quently seek attention initially because of irreg- described masculinized women with amenor- ular menses, hirsutism, or , but PCOS rhea, sterility, and enlarged containing has a long prodrome with detectable abnor- multiple cysts. The syndrome was placed in malities throughout the life cycle of affected the gynecologic realm for control of chronic women. The earliest manifestations of PCOS anovulation, abnormal menstrual bleeding, are discernible in the peripubertal years. and infertility. Ovarian and insulin By the early 1980s, this symptom complex resistance develop with increased frequency in had been linked to hyperinsulinemia and adolescent girls who have premature pub- impaired glucose tolerance.3,4 The connection arche.11,12 In the early reproductive period, to an insulin post-receptor defect was isolated chronic anovulation results in reduced rates of in women with PCOS in the early 1990s.5 As a conception. When pregnancy is achieved, it result of these recent associations, attention is frequently terminates in spontaneous, first- now focused on treating the central deficits trimester loss or is associated with gestational and fundamental problems of hyperandro- diabetes.6 Approximately 25 to 30 percent of genism, hyperinsulinemia, abnormal serum these women show impaired glucose tolerance lipid levels, and obesity that have broader by the age of 30, and 8 percent of women with health implications (Table 1).3,6-10 This new PCOS develop frank type 2 diabetes mellitus information profoundly alters our view of the annually.7 gravity of this condition. Family physicians Markers of premature coronary artery and

AUGUST 15, 2003 / VOLUME 68, NUMBER 4 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 697 tension, and coronary artery disease compared with con- TABLE 1 trol patients. PCOS appears to follow a familial distribu- Intermediate and Long-Term Consequences tion; 40 percent of the sisters and 20 percent of the moth- Associated with PCOS ers of affected women also have the syndrome to varying degrees.15 Infertility Hypertension Recurrent spontaneous abortion Type 2 diabetes mellitus Clinical Features Depression/anxiety Coronary atherosclerosis In many women the symptoms are easily recognizable, Dyslipidemias Cerebrovascular accidents but ethnicity influences the extent of symptoms, especially Total cholesterol (elevated) Endometrial carcinoma with regard to hirsutism and obesity. Therefore, taking a LDL cholesterol (elevated) diligent history with regard to menstrual patterns is cru- HDL2 cholesterol (decreased) Triglycerides (elevated) cial to help establish the diagnosis. The National Institute of Child Health and Development16 held a consensus meeting to develop the following diagnostic criteria for NOTE: These abnormalities may be identified in women with PCOS at various life stages. Listed in order from most common to least PCOS: (1) clinical or biochemical evidence of hyperan- common. drogenism; (2) oligo-ovulation; and (3) exclusion of other PCOS = polycystic ovary syndrome; LDL = low-density lipoprotein; known disorders, such as congenital adrenal hyperplasia HDL = high-density lipoprotein. or hyperprolactinemia. Information from references 3, and 6 through 10. HYPERANDROGENISM The wide spectrum of manifestations ranges from mild acne and increased terminal (coarse) hair growth in midline cerebrovascular disease are prevalent. Women with poly- structures (face, neck, abdomen), to android changes in cystic ovaries are seen to have more extensive coronary body habitus, with waist-to-hip ratios of more than 1. Vari- artery disease by angiography.8 In two case-control stud- ations are influenced by ethnicity,17 as well as coexisting con- ies,9,10 women in their 40s had greater intima-medial thick- ditions (such as hyperthyroidism) that alter ness of the carotid vessels, and more atherogenic lipid pro- biosynthesis. For example, Asian women with PCOS are files: increased total and low-density lipoprotein (LDL) rarely hirsute, but hirsutism is a frequent finding in black cholesterol and triglyceride levels, and decreased high-den- women with PCOS. Yet the actual incidences of hyperan- sity lipoprotein (HDL) cholesterol levels.9,10 drogenemia and insulin resistance do not show a racial These metabolic abnormalities are compounded by the predilection. prevalence of obesity, which occurs in more than 65 per- In addition, nonhirsute women with oligo-ovulation cent of women with PCOS.3 Abnormal androgen produc- may have laboratory evidence of hyperandrogenism. tion declines as menopause approaches (as it does in Frank or rapid “virilization” involving clitoromegaly, vocal women without PCOS), and menstrual patterns somewhat chord thickening, or male-pattern baldness is rare in normalize. However, in retrospective cohort studies,13,14 patients with PCOS and, when present, suggests another perimenopausal and postmenopausal women with a his- cause of hyperandrogenism, such as adrenal disorders or tory of PCOS had increased rates of type 2 diabetes, hyper- androgen-producing tumors (Table 2).18

OLIGO-OVULATION Diagnostic criteria for polycystic ovary syndrome Oligo-ovulation manifests as menstrual irregularity and occurs in 70 percent of women with PCOS. Among include (1) clinical or biochemical evidence of women with more regular menses, many have variable hyperandrogenism, (2) oligo-ovulation, and (3) degrees of ovulatory dysfunction. Often the menstrual for- exclusion of other known disorders, such as mula (i.e., three to five days of menstrual flow every 28 to adrenal hyperplasia or hyperprolactinemia. 35 days) occurs for the first one to two years after menar- che (which occurs at the normal age), but menses then

698 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 4 / AUGUST 15, 2003 PCOS

become less frequent, occurring every 45 to 365 days. Because the estrogen from ovarian and adipose tissues Bleeding can be unpredictable, heavy, and pro- stimulates proliferation of that is not stabi- longed, and chronic endometrial proliferation can lized by post-ovulatory progesterone, bleeding can be result in carcinoma. unpredictable, heavy, and prolonged. Chronic endometrial proliferation can result in carcinoma.

SYMPTOMS WITH VARIABLE FREQUENCY Diagnostic Evaluation Obesity. More than 65 percent of women with PCOS Although there is no consensus as to which laboratory have a body mass index exceeding 27. The fat distribution tests should be used to diagnose PCOS, most physicians often is abdominal/visceral, similar to that frequently asso- agree that the evaluation should screen for hyperandro- ciated with metabolic abnormalities (e.g., hypertension, genemia as well as for abnormalities that have serious dyslipidemia, insulin resistance, glucose intolerance). Most health consequences. Often, the clinical picture is readily women deny childhood obesity and describe normal apparent from the history and physical findings. Thus, test- weight until after menarche. Significant weight gain ing for parameters known to be abnormal in women with appears in the mid-teens and accelerates in the later teens PCOS, such as luteinizing hormone (LH) and follicle- and early 20s. stimulating hormone (FSH) ratios, is unnecessary, redun- The presence of obesity also is influenced by ethnicity. It dant, and expensive. is most common in Hispanic, black, and white women, less In the author’s opinion, the evaluation should follow striking in women of Mediterranean descent, and rare in these principles: exclude other etiologies of , Asian women.17 Obesity is likely to facilitate the metabolic such as prolactin or thyroid abnormalities; exclude other abnormalities of PCOS, as evidenced by the reduction in causes of hyperandrogenism; exclude glucose intolerance; insulin resistance and restoration of cyclic menses follow- and detect insulin resistance and lipid abnormalities. ing weight loss.19 A 1982 study,20 which has been con- firmed by later research, showed that a 10 to 15 percent LABORATORY EVALUATION weight reduction resulted in spontaneous conception in Normal testosterone determinations in the hirsute patient more than 75 percent of obese patients with PCOS. can be misleading, partially because of inherent variation in Acanthosis Nigricans. These velvety, raised skin deposits in intertriginous areas are associated with insulin resis- tance and result from insulin stimulation of the basal lay- TABLE 2 ers of the epidermis. When found in conjunction with Differential Diagnosis of Hyperandrogenism hyperandrogenism, the condition is termed HAIR-AN syndrome (hyperandrogenic-insulin resistant–acanthosis Percentage of 21 nigricans); it occurs in 2 to 5 percent of hirsute women. Most common causes hyperandrogenic women The majority of women with PCOS (70 percent) are insulin resistant, but hyperinsulinemia is far more severe in PCOS 65 to 85 women with HAIR-AN syndrome. HAIR-AN syndrome 1 to 5 Polycystic Ovaries. Ovaries with multiple, small (less than Nonclassic adrenal hyperplasia 1 to 8 10 mm) follicular cysts surrounding the ovarian stroma are Androgen-producing tumors Rare found in 16 to 25 percent of normal women and in female Idiopathic 15 patients with ammenorrhea caused by other etiologies.22 Nearly 80 percent of women with hyperandrogenism have PCOS = polycystic ovary syndrome; HAIR-AN = hyperandrogenic- polycystic ovaries,23 but these may not be present at the time insulin resistant—acanthosis nigricans. of evaluation in women who have used oral contraceptive Adapted with permission from Azziz R. Hirsutism. In: Droege- pills (OCPs), insulin-sensitizing agents, or other forms of mueller W, Sicarra JJ, eds. Gynecology and obstetrics.Vol 5. ovarian suppression. Therefore, the presence of polycystic Philadelphia: Lippincott, 1994:1-22. ovaries on ultrasonography is not a diagnostic essential.

AUGUST 15, 2003 / VOLUME 68, NUMBER 4 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 699 TABLE 3 Laboratory Investigation of PCOS

Test Normal value Purpose

-hCG < 5 mIU per mL (< 5 IU per L) Exclude pregnancy TSH 0.5 to 4.5 µU per mL (0.5 to 4.5 mU per L) Exclude thyroid dysfunction Prolactin < 20 ng per mL (< 20 µg per L) Exclude hyperprolactinemia Testosterone (total) < 20 ng per dL (< 0.7 nmol per L) Exclude androgen-secreting neoplasm Testosterone (free) 20 to 30 years—0.06 to 2.57 pg per mL Establish diagnosis or monitor therapy (0.20 to 8.90 pmol per L) 40 to 59 years—0.4 to 2.03 pg per mL (1.40 to 7.00 pmol per L) DHEAS 600 to 3,400 ng per mL (1.6 to 9.2 µmol per L) Exclude androgen-secreting neoplasm Androstenedione 0.4 to 2.7 ng per mL (1.4 to 9.4 nmol per L) Establish diagnosis 17-hydroxyprogesterone Follicular phase < 2 µg per L (6.1 nmol per L) Exclude NCAH Fasting insulin < 20 µU per mL (< 144 pmol per L) Exclude hyperinsulinemia Fasting glucose 65 to 119 mg per dL (3.6 to 6.6 mmol per L) Exclude type 2 diabetes or glucose intolerance Fasting glucose: insulin ratio ≥ 4.5 Exclude insulin resistance Cholesterol (total) 150 to 200 mg per dL (1.5 to 2 g per L) Monitor lifestyle changes HDL cholesterol 35 to 85 mg per dL (0.9 to 2.2 mmol per L) Monitor lifestyle changes LDL cholesterol 80 to 130 mg per dL (2.1 to 3.4 mmol per L) Monitor lifestyle changes Pelvic ultrasonography Monitor lifestyle changes Endometrial biopsy Negative for hyperplasia/malignancy Exclude malignancy or hyperplasia

NOTE: Diagnosis of PCOS established by exclusion of other causes of or hyperandrogenism. Other tests may be of benefit in monitoring therapy. PCOS = polycystic ovary syndrome; -hCG = beta subunit human chorionic gonadotropin; TSH = thyroid-stimulating hormone; DHEAS = dehydroepiandrosterone sulfate; NCAH = nonclassic adrenal hyperplasia; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

commercial testing methods.24 However, bioavailable (free) Both free testosterone and sex hormone-binding globu- testosterone levels may support the diagnosis, especially in a lin may be useful in monitoring the efficacy of androgen nonhirsute woman with other signs and symptoms of suppression therapy. Total testosterone levels greater than PCOS. Hyperandrogenemia also might be established by 20 ng per dL (0.7 nmol per L) or DHEAS levels greater elevated serum levels of dehydroepiandrosterone sulfate than 700 ng per mL (1.9 µmol per L) are suggestive of (DHEAS) and androstenedione.4 androgen-secreting tumors; these patients should be referred for gynecologic investigation.25 Morning 17-hydroxyprogesterone (17-OHP) determi- nation is important to exclude nonclassic adrenal hyperpla- The Author sia secondary to 21-hydroxylase deficiency, which is present MARILYN R. RICHARDSON, M.D., is clinical assistant professor of in 1 to 8 percent of hirsute women.26 When elevated 17- obstetrics and gynecology in the Division of Reproductive Endocrinol- ogy and Infertility at the University of Kansas Medical Center, Kansas OHP is discovered, the next step should be a short adreno- City, Kan. She received her medical degree from the University of corticotropic hormone stimulation test to further delineate Kansas School of Medicine, Kansas City, and completed a residency in the enzymatic defect. The ratio of LH to FSH is greater than obstetrics and gynecology at the University of Missouri–Kansas City School of Medicine, Truman Medical Center, Kansas City, and a fellow- 3:1 in about 30 percent of women with PCOS and may be ship in reproductive endocrinology and infertility at the University of diagnostically helpful in nonhirsute women with mild ovu- Texas Health Science Center at Dallas. latory dysfunction, but this determination is not routinely Address correspondence to Marilyn R. Richardson, M.D., University of necessary if the clinical picture is otherwise clear. Kansas Medical Center, Department of Obstetrics and Gynecology, Divi- Because nearly 30 percent of women with PCOS have sion of Reproductive Endocrinology and Infertility, 3901 Rainbow Blvd., Kansas City, KS 66160 (e-mail: [email protected]). Reprints are impaired glucose tolerance, determinations of glucose tol- not available from the author. erance and insulin resistance are of paramount impor-

700 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 4 / AUGUST 15, 2003 TABLE 4 Medical Treatment Options in PCOS

Drug Suggested dosage Benefits* Cost (generic)†

Oral contraceptives 21 days per month 1, 2, 3 $27.00 to 32.00 Medroxyprogesterone 10 mg daily for 10 days 2 12.00 (5.00 to 7.00 ) acetate (Provera) Micronized progesterone 400 mg daily for 10 days 2 30.00 (Prometrium) Spironolactone (Aldactone) 50 to 200 mg daily 1, 2‡ 30.00 to 99.00 (25.00 to 85.00) Metformin (Glucophage) 500 to 850 mg three times daily 1, 2, 3, 4, 5, 6 70.00 to 120.00 (63.00 to 108.00) Clomiphene citrate (Serophene) 50 to 150 mg for five days 2, 3, 4 49.00 to 147.00 (29.00 to 103.80) Gonadotropin (FSH/LH) Individualized‡ 2, 3, 4 600.00 to 3,000.00

PCOS = polycystic ovary syndrome; FSH = follicle-stimulating hormone; LH = luteinizing hormone. *—1 = Suppression of hyperandrogenism; 2 = restore menstrual cyclicity; 3 = prevent endometrial hyperplasia; 4 = induce/facilitate ovu- lation; 5 = facilitate weight loss; 6 = reduce hyperinsulinemia. †—Estimated cost to the pharmacist for one month of therapy based on average wholesale prices in Red book. Montvale, N.J.: Medical Economics Data, 2002. Cost to the patient will be higher, depending on prescription filling fee. ‡—Possible.

tance. One approach is to perform standard oral glucose choices should be based on the woman’s most pressing tolerance testing with insulin levels. Peak levels of insulin concern and her stage of reproductive life (Figure 1). Given that exceed 100 µU per mL (718 pmol per L) are suggestive the current awareness of the long-term consequences asso- of insulin resistance. This test may be unnecessarily cum- ciated with PCOS, the physician carries the responsibility bersome and expensive for general screening, however, and of tailoring therapy to add preventive benefits. In addition, the author’s practice is to reserve this test for use in women cosmetic alterations can result in depression and with- with a family history of glucose intolerance, morbid obe- drawal from social and career pursuits. Thus, the physician sity, or other symptoms suggestive of diabetes. should be armed with information about removal of A more efficient assessment may be to use the ratio of unwanted hair. Shaving and depilation are the most effi- fasting levels of glucose to insulin. When less than 4.5, this cient short-term means for terminal hair removal while ratio has a significant correlation with insulin resistance and initiating androgen suppression using some of the modal- has been studied for use as a screening test in obese patients ities described below. with PCOS. It combines sensitivity (95 percent) and speci- ficity (84 percent) for insulin resistance, with positive and STEROID HORMONES negative predictive values of 87 percent and 97 percent in OCPs are the most efficient means of androgen sup- obese patients with PCOS.27 This predictive capacity may pression (ovarian as well as adrenal), and nearly any com- not hold true in nonobese women with PCOS. bination OCP is effective in treating PCOS. This therapy The author includes assessments of total, HDL, and LDL results in lower and static LH levels without surges. The cholesterol levels as well as triglyceride levels to help in estrogen component stimulates hepatic production of sex planning and follow-up of recommended dietary modifi- hormone-binding globulin that reduces bioavailable cations to reduce obesity and cardiovascular risk. Finally, androgen and can reduce hirsutism and acne. The prog- endometrial biopsy is helpful to rule out endometrial estin component provides competitive antagonism to hyperplasia in patients with prolonged amenorrhea (more than five months). A list of laboratory tests that may help to identify patients with PCOS is provided in Table 3. A ratio of less than 4.5 of fasting glucose to Treatment insulin levels correlates significantly with insulin The primary goal of all forms of therapy is to suppress resistance and has been studied for use as a insulin-facilitated, LH-driven androgen production. screening test in obese patients with polycystic Although numerous medications (Table 4) and protocols ovary syndrome. are effective in reducing insulin and androgen levels, the

AUGUST 15, 2003 / VOLUME 68, NUMBER 4 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 701 Management of Polycystic Ovary Syndrome

Women who wish to achieve Clomiphene citrate Women who need Combination oral pregnancy/ovulation induction or gonadotropins contraception contraceptive pills

Treatment Treatment Hirsutism, acne Depilatory/electrolysis Depilatory/electrolysis Hirsutism, acne Spironolactone (Aldactone) Obesity Lifestyle modification

Obesity Lifestyle modification Insulin resistance, Metformin (Glucophage) oligomenorrhea Insulin resistance, Metformin (Glucophage) oligomenorrhea

FIGURE 1. Management of polycystic ovary syndrome. After the primary concern is identified, the patient can decide if contraception or fertility is preferred. Lifestyle modification is a central measure in either case. androgen at its receptors, reducing the action of testos- terone at the target organ. ANTIANDROGENS Newer formulations contain progestins of lower andro- Therapy with spironolactone (Aldactone) has a direct genicity, such as norgestimate, desogestrel, and gestodene. suppressive effect on enzymes in the androgen biosynthetic OCPs can be used alone or in conjunction with antiandro- pathway. Because of its structural similarity to testosterone, gens, gonadotropin-releasing hormone agonists, or it can competitively inhibit binding and insulin-sensitizing agents. Restoration of the menstrual is useful in the treatment of hirsutism. Three of six open cycle and prevention of endometrial hyperplasia are addi- clinical trials showed improvement in hirsutism, but results tional benefits. of double-blind placebo-controlled trials were not as posi- Hirsute women should be counseled that regression of tive.28 One study29 has shown that spironolactone can terminal hair growth during OCP therapy is a slow reduce the caliber and growth rate of terminal hair. Dosages process, requiring up to eight months for noticeable bene- as high as 200 mg per day are tolerated, and menses some- fits. It is appropriate to institute permanent methods of times resume. This agent is most effective when combined hair removal by way of electrolysis or laser ablation after with OCPs; some form of contraception is advisable when suppression of hyperandrogenism has been achieved. it is used alone. A newly released formulation of OCP con- Because these women are highly estrogenized (as a result tains an analog of spironolactone, drospirenone. Drospire- of peripheral conversion of androgenic precursors), none combined with ethinyl estradiol (Yasmin) is indicated menses can be induced by administration of progesta- as a contraceptive. tional agents for approximately 10 days. Women should be advised that their cycles are not re-established by this treat- ASSISTED FERTILITY ment, and that if it is not repeated at two- or three-month Clomiphene citrate (Serophene) or gonadotropins can intervals, unchecked endometrial growth can result in be used to establish menses but should be reserved for use endometrial hyperplasia. If menstrual bleeding does not in patients who wish to become pregnant. Because the occur within 14 days of completion of progesterone woman with PCOS is uniquely sensitive to these agents and administration, another etiology for amenorrhea rather risks higher rates of ovarian hyperstimulation and multiple than PCOS should be sought. Progesterone administration gestation,30 specialty referral for this therapy is recom- does not provide relief from any other symptoms or pre- mended. Clomiphene administration will result in ovula- vent any of the long-term conditions. It is useful on a tion in 50 to 60 percent of cases, in pregnancy in 30 percent, scheduled basis only for menstrual regulation. and in multiple gestation (twins or greater) in 3 percent.

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Although the body of data is limited, it is suggested that excessive or prolonged exposure to clomiphene citrate Lifestyle modifications with weight loss have (more than 12 months) could increase the risk of ovarian achieved pregnancy rates as high as 60 percent 31 cancer. When clomiphene fails, gonadotropin administra- without medical intervention. tion frequently is successful in helping women to achieve pregnancy (70 percent), but it requires self-injection, is costly, and carries an even higher rate of hyperstimulation and multifetal pregnancy (as high as 30 percent).32 it brings about the greatest global improvement in car- diovascular risks, insulin sensitivity, and menstrual pat- INSULIN REDUCTION terns; it is most difficult because of the compliance issue. Metformin (Glucophage), a biguanide and insulin-sen- Weight loss should not be rapid or drastic but should be sitizing agent, has been used to restore menstrual cyclic- achieved through consistent lifestyle modification that ity and induce ovulation in PCOS without the use of includes gentle exercise, intake of dietary carbohydrates additional fertility drugs. Use of this agent is associated with a low glycemic index, and a reduced intake of fats with reductions in serum levels of bioavailable androgen, and simple sugars. Severe dietary deprivation is uni- LH, and atherogenic lipids. Levels of plasminogen activa- formly unsuccessful. tor inhibitor I and Lp(a) lipoprotein also were reduced.33 No single food plan is recommended, but frequent feed- There are no data to show a benefit in women who are ings (four to six times per day) are important to avoid not insulin resistant, but a few physicians support its hypoglycemia and hunger. Hypoglycemia leads to cravings empiric use. and poor food choices that, in turn, result in simple sugar Metformin is presently classified as a category “B” risk in intake and reactive hyperinsulinemia. In the experience of pregnancy, which indicates that there are no apparent fetal the author, most women respond well to the admonition defects associated with its use in the late trimester of preg- to eat more food more frequently to lose weight. nancy, based on animal studies. Because the human effects In addition to the metabolic improvements, successful of first-trimester use are unknown, discontinuation of weight loss has the benefit of improving body image, therapy at the onset of pregnancy confirmation has been reducing depression, and restoring a sense of control. Pro- standard. However, a recent prospective study of women grams that have targeted this issue alone have achieved with PCOS who continued metformin therapy through pregnancy rates as high as 60 percent without medical the first trimester of pregnancy showed no evidence of intervention.35 There are no data to support the use of fetal harm, calling into question this recommendation.34 lipid-lowering drugs in women younger than 40 years, but The rate of early spontaneous abortion was reduced dietary regulation should be encouraged. Family physi- from 73 percent without metformin to 10 percent. In our cians should monitor blood pressure elevations and smok- clinical setting, the initial dosage of 500 mg is given at bed- ing cessation for further cardiovascular protection. time each night for one week to reduce the occurrence of Knowledge gained over the past 60 years has carried gastrointestinal side effects and is increased by 500 mg per PCOS beyond the realm of gynecology and infertility, and week to a total dosage of 1,500 mg per day in divided doses. warrants heightened attention from physicians who will Insulin, glucose, and androgen levels are retested after eight focus on the functional abnormalities that have serious weeks. If improvement is not shown, the dosage is long-term consequences. It is important to recognize that increased to 2,550 mg. Menses often will occur within this PCOS is an entity with a long lifespan, requiring “control” treatment time. If fertility is desired, ovulation induction rather than “cure,” and that therapies will change with the agents can be added. Metformin therapy is associated with stage of life (Figure 1). A considerable armamentarium of a slight risk of lactic acidosis and is not used in patients therapies exists for the family physician, using specialty with impaired liver or renal function. referral for patients with intractable , infertility, or dermatologic problems. LIFESTYLE MODIFICATION

The most successful but difficult therapy to “adminis- The author indicates that she does not have any conflicts of inter- ter” is weight loss. Weight loss is most successful because est. Sources of funding: none reported.

AUGUST 15, 2003 / VOLUME 68, NUMBER 4 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 703 PCOS

REFERENCES nicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet 1. Hull MG. Epidemiology of infertility and polycystic ovarian disease: Gynecol 1992;167:1807-12. endocrinological and demographic studies. Gynecol Endocrinol 18. Azziz R. Hirsutism. In: Droegemueller W, Sicarra JJ, eds. Gynecol- 1987;1:235-45. ogy and obstetrics. Vol 5. Philadelphia: Lippincott, 1994:1-22. 2. Stein IL, Leventhal ML. Amenorrhea associated with bilateral poly- 19. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed cystic ovaries. Am J Obstet Gynecol 1935;29:181-91. MJ, et al. Improvement in endocrine and ovarian function during 3. Ehrmann DA. Obesity and glucose intolerance in androgen excess. dietary treatment of obese women with polycystic ovary syn- In: Azziz R, Nestler JE, Dewailly D, eds. Androgen excess disorders drome. Clin Endocrinol 1992;36:105-11. in women. Philadelphia: Lippincott-Raven, 1997:705-12. 20. Bates GW, Whitworth NS. Effect of body weight reduction on 4. Dunaif A, Hoffman AR, Scully RE, Flier JS, Longcope C, Levy LJ, et plasma in obese, infertile women. Fertil Steril 1982; al. Clinical, biochemical, and ovarian morphologic features in 38:406-9. women with acanthosis nigricans and masculinization. Obstet 21. Azziz R. The hyperandrogenic-insulin-resistant acanthosis nigri- Gynecol 1985;66:545-52. cans syndrome: therapeutic response. Fertil Steril 1994;61:570-2. 5. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin 22. Polson DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries— receptor serine phosphorylation in cultured fibroblasts and in a common finding in normal women. Lancet 1988;1:870-2. skeletal muscle. A potential mechanism for insulin resistance in 23. O’Driscoll JB, Mamtora H, Higginson J, Pollock A, Kane J, Ander- the polycystic ovary syndrome. J Clin Invest 1995;96:801-10. son DC. A prospective study of the prevalence of clear-cut 6. Vollenhoven B, Clark S, Kovacs G, Burger H, Healy D. Prevalence endocrine disorders and polycystic ovaries in 350 patients pre- of gestational diabetes mellitus in polycystic ovarian syndrome senting with hirsutism or androgenic alopecia. Clin Endocrinol (PCOS) patients pregnant after ovulation induction with gonado- 1994;41:231-6. trophins. Aust N Z J Obstet Gynaecol 2000;40:54-8. 24. Boots LR, Potter S, Potter D, Azziz R. Measurement of total serum 7. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and pre- testosterone levels using commercially available kits: high degree dictors of risk for type 2 diabetes mellitus and impaired glucose toler- of between-kit variability. Fertil Steril 1998;69:286-92. ance in polycystic ovary syndrome: a prospective, controlled study in 25. Derksen J, Nagesser SK, Meinders AE, Haak HR, van de Velde CJ. 254 affected women. J Clin Endocrinol Metab 1999;84:165-9. Identification of virilizing adrenal tumors in hirsute women. N Engl 8. Birdsall MA, Farquhar CM, White HD. Association between poly- J Med 1994;331:968-73. cystic ovaries and extent of coronary artery disease in women hav- 26. Azziz R, Zacur HA. 21-Hydroxylase deficiency in female hyperan- ing cardiac catheterization. Ann Intern Med 1997;126:32-5. drogenism: screening and diagnosis. J Clin Endocrinol Metab 9. Guzick DS, Talbott EO, Sutton-Tyrrell K, Herzog HC, Kuller LH, 1989;69:577-84. Wolfson SK Jr. Carotid atherosclerosis in women with polycystic 27. Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio ovary syndrome: initial results from a case-control study. Am J is a useful measure of insulin sensitivity in women with polycystic Obstet Gynecol 1996;174:1224-9. ovary syndrome. J Clin Endocrinol Metab 1998;83:2694-8. 10. Talbott E, Clerici A, Berga SL, Kuller L, Guzick D, Detre K, et al. 28. McMullen GR, Van Herle AJ. Hirsutism and the effectiveness of Adverse lipid and coronary heart disease risk profiles in young spironolactone in its management. J Endocrinol Invest 1993;16: women with polycystic ovary syndrome: results of a case-control 925-32. study. J Clin Epidemiol 1998;51:415-22. 29. Spritzer PM, Lisboa KO, Mattiello S, Lhullier F. Spironolactone as a 11. Ibanez L, Potau N, Virdis R, Zampolli M, Terzi C, Gussinye M, et al. single agent for long-term therapy of hirsute patients. Clin Postpubertal outcome in girls diagnosed of premature pubarche Endocrinol 2000;52:587-94. during childhood: increased frequency of functional ovarian 30. Lobo RA, Gysler M, March CM, Goebelsmann U, Mishell DR Jr. hyperandrogenism. J Clin Endocrinol Metab 1993;76:1599-603. Clinical and laboratory predictors of clomiphene response. Fertil 12. Ibanez L, Potau N, Zampolli M, Prat N, Virdis R, Vicens-Calvet E, et Steril 1982;37:168-74. al. Hyperinsulinemia in postpubertal girls with a history of prema- 31. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian ture pubarche and functional ovarian hyperandrogenism. J Clin tumors in a cohort of infertile women. N Engl J Med 1994; Endocrinol Metab 1996;81:1237-43. 331:771-6. 13. Cibula D, Cifkova R, Fanta M, Poledne R, Zivny J, Skibova J. 32. Wang CF, Gemzell C. The use of human gonadotropins for the Increased risk of non-insulin dependent diabetes mellitus, arterial induction of ovulation in women with polycystic ovarian disease. hypertension and coronary artery disease in perimenopausal Fertil Steril 1980;33:479-86. women with a history of the polycystic ovary syndrome. Hum 33. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin Reprod 2000;15:785-9. therapy in polycystic ovary syndrome reduces hyperinsulinemia, 14. Dahlgren E, Johansson S, Lindstedt G, Knutsson F, Oden A, Janson insulin resistance, hyperandrogenemia, and systolic blood pres- PO, et al. Women with polycystic ovary syndrome wedge resected sure, while facilitating normal menses and pregnancy. Metabolism in 1956 to 1965: a long-term follow-up focusing on natural his- 1994;43:647-54. tory and circulating hormones. Fertil Steril 1992;57:505-13. 34. Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Contin- 15. Legro RS, Driscoll D, Strauss JF 3d, Fox J, Dunaif A. Evidence for a uing metformin throughout pregnancy in women with polycystic genetic basis for hyperandrogenemia in polycystic ovary syn- ovary syndrome appears to safely reduce first-trimester sponta- drome. Proc Natl Acad Sci U S A 1998;95:14956-60. neous abortion: a pilot study. Fertil Steril 2001;75:46-52. 16. National Institutes of Health Consensus Meeting on PCOS. In: 35. Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of repro- Dunaif A, ed. Current issues in endocrinology and metabolism. ductive potential by lifestyle modification in obese polycystic ovary Boston: Blackwell Scientific, 1992. syndrome: role of insulin sensitivity and luteinizing hormone. J Clin 17. Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA. Does eth- Endocrinol Metab 1999;84:1470-4.

704 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 4 / AUGUST 15, 2003